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Development of Novel p38 MAPK Inhibitors as Therapeutics for CNS Disorders

开发新型 p38 MAPK 抑制剂作为中枢神经系统疾病的治疗药物

基本信息

批准号：
8286256
负责人：
Daniel Martin Watterson
金额：
$ 29.35万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8286256
关键词：
AIDS Dementia Complex Address Age related macular degeneration Alzheimer&apos s Disease Amines Amyloid beta-Protein Amyotrophic Lateral Sclerosis Animal Model Area Arts Attenuated Bioavailable Biological Biological Availability Biology Blood - brain barrier anatomy Brain Budgets Cardiotoxicity Central Nervous System Diseases Chemicals Chemistry Clinical Clinical Research Clinical Trials Data Databases Development Disease Disease Progression Drug Kinetics Epilepsy Exercise Failure Feasibility Studies Feedback Foundations Functional disorder Future Goals Guidelines Health Human In Vitro Inflammatory Infusion procedures Injury Intellectual Property Investigation Lead Legal patent Licensing Link Liver MAP Kinase Gene MAPK14 gene Medical Medicine Metabolic Metabolism Mitogen-Activated Protein Kinase Inhibitor Modeling Molecular Molecular Target Molecular Weight Multiple Sclerosis Neurodegenerative Disorders Neuroglia Neurologic Neurologic Deficit Neurological outcome Oral Outcome Output Parkinson Disease Pathology Penetrance Performance Peripheral Pharmaceutical Chemistry Pharmaceutical Economics Pharmaceutical Preparations Phase Probability Process Production Property Protein Kinase Inhibitors Protein-Serine-Threonine Kinases Publications Regulation Research Risk Role Safety Savings Screening procedure Senile Plaques Specific qualifier value Staging Stroke Structure Synapses Synthesis Chemistry Technology Transfer Testing Therapeutic Time Tissues Toxic effect Toxicology Transgenic Mice Translating Traumatic Brain Injury Universities Up-Regulation attenuation base central nervous system injury chemical stability clinical effect cost cytokine design drug development drug discovery efficacy testing experience in vivo inhibitor/antagonist injured knowledge base lipophilicity meetings mouse model nervous system disorder novel painful neuropathy physical property pre-clinical programs protein kinase inhibitor response scaffold small molecule success therapeutic target uptake

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this research program is the discovery of potentially disease-modifying therapies for neurodegenerative disorders. This proposal tests the hypothesis that novel p38 MAPK inhibitors that are orally bioavailable, have good brain uptake, and are non-toxic can be developed into a new class of therapeutics for CNS disorders. The proposed research seeks to develop p38 MAPK inhibitors that can restore pathology associated increased proinflammatory cytokine production toward basal levels with positive neurologic outcomes in animal models. The linkage to the long term goals is that the deliverables emerging from successful completion of the proposed studies will form the foundation of follow-on drug development campaigns for neurodegenerative disorders. Clinical studies have provided a linkage among neurodegenerative disorders, glia activation and increased levels of proinflammatory cytokines, with feasibility studies using macromolecular therapeutics suggestive of a positive clinical effect of proinflammatory cytokine attenuation in Alzheimer's disease. Prior art in animal models has demonstrated a pathophysiology progression role and enhanced sensitivity to synaptic dysfunction and neurologic deficits in animal models where brain proinflammatory cytokine levels are increased. Attenuation of neurologic deficits can be restored by inhibiting the increase in proinflammatory cytokine production. Therefore, an accumulating body of evidence indicates the potential of targeting proinflammatory cytokine up-regulation for attenuation of CNS dysfunction. However, there is an unmet need for bioavailable, CNS-penetrant small molecules amenable to clinical development. We propose to use our integrative drug discovery platform that combines "smart" chemistry with "smart" biology to discover novel lead compounds with attractive physical properties and high potential for CNS penetrance, safety and efficacy, followed by medicinal chemistry refinement into candidates for future clinical development. The molecular target is the serine/threonine protein kinase p381MAPK, a key regulator of proinflammatory cytokine production and an established therapeutic target for peripheral tissue diseases where increased proinflammatory cytokine levels are part of the disease progression mechanism. Specifically, we propose to: design, synthesize, and refine novel p381MAPK inhibitors with potential for oral bioavailability and CNS penetrance; screen compounds to identify orally bioavailable, CNS-penetrant, non-toxic, stable lead compounds that are selective suppressors of increased cytokine production in the brain; and test selected lead compounds for efficacy in Alzheimer's disease-relevant animal models. Successful completion of the proposed investigations will provide a knowledgebase and novel lead compounds for future IND-enabling preclinical toxicology and pharmacokinetics required for initiation of later clinical investigations. PUBLIC HEALTH RELEVANCE Successful completion of the proposed investigations will provide novel, efficacious compounds required for clinical development of new therapies for neurological disorders.

描述（由申请人提供）：本研究项目的长期目标是发现神经退行性疾病的潜在疾病改善疗法。这一提议验证了一种假设，即新型的p38 MAPK抑制剂具有口服生物利用性，具有良好的脑摄取性，并且无毒，可以发展成为一种新的治疗中枢神经系统疾病的药物。该研究旨在开发p38 MAPK抑制剂，在动物模型中可以将病理相关的促炎细胞因子产生增加恢复到基础水平，并具有积极的神经预后。与长期目标的联系是，成功完成拟议研究所产生的成果将构成后续神经退行性疾病药物开发运动的基础。临床研究已经提供了神经退行性疾病、胶质细胞激活和促炎细胞因子水平升高之间的联系，使用大分子疗法的可行性研究表明，促炎细胞因子衰减在阿尔茨海默病中具有积极的临床效果。动物模型中的现有技术已经证明，在脑促炎细胞因子水平增加的动物模型中，具有病理生理进展作用，对突触功能障碍和神经功能缺陷的敏感性增强。通过抑制促炎细胞因子产生的增加，可以恢复神经功能缺损的衰减。因此，越来越多的证据表明，靶向促炎细胞因子上调有可能减轻中枢神经系统功能障碍。然而，对生物可利用的、cns渗透的、适合临床开发的小分子的需求尚未得到满足。我们建议使用我们的综合药物发现平台，将“智能”化学与“智能”生物学相结合，发现具有吸引人的物理性质和高CNS外显率，安全性和有效性潜力的新型先导化合物，然后进行药物化学细化，成为未来临床开发的候选药物。分子靶点是丝氨酸/苏氨酸蛋白激酶p381MAPK，它是促炎细胞因子产生的关键调节因子，也是外周组织疾病的既定治疗靶点，促炎细胞因子水平升高是疾病进展机制的一部分。具体来说，我们建议：设计、合成和改进具有口服生物利用度和中枢神经系统外显性潜力的新型p381MAPK抑制剂；筛选化合物，以确定口服生物可利用、cns渗透、无毒、稳定的先导化合物，这些先导化合物是大脑中细胞因子产生增加的选择性抑制因子；并在阿尔茨海默病相关动物模型中测试选定的先导化合物的功效。拟议研究的成功完成将为未来启动临床研究所需的临床前毒理学和药代动力学提供知识库和新的先导化合物。拟议研究的成功完成将为神经系统疾病新疗法的临床开发提供新的、有效的化合物。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Retention of normal glia function by an isoform-selective protein kinase inhibitor drug candidate that modulates cytokine production and cognitive outcomes.

DOI：
10.1186/s12974-017-0845-2
发表时间：
2017-04-05
期刊：
Journal of neuroinflammation
影响因子：
9.3
作者：
Zhou Z;Bachstetter AD;Späni CB;Roy SM;Watterson DM;Van Eldik LJ
通讯作者：
Van Eldik LJ

A novel p38 alpha MAPK inhibitor suppresses brain proinflammatory cytokine up-regulation and attenuates synaptic dysfunction and behavioral deficits in an Alzheimer's disease mouse model.

一种新型的p38 alpha MAPK抑制剂抑制了脑促炎细胞因子上调，并减轻阿尔茨海默氏病小鼠模型中的突触功能障碍和行为缺陷。

DOI：
10.1186/1742-2094-4-21
发表时间：
2007-09-04
期刊：
JOURNAL OF NEUROINFLAMMATION
影响因子：
9.3
作者：
Munoz, Lenka;Ranaivo, Hantamalala Ralay;Roy, Saktimayee M.;Hu, Wenhui;Craft, Jeffrey M.;McNamara, Laurie K.;Chico, Laura Wing;Van Eldik, Linda J.;Watterson, D. Martin
通讯作者：
Watterson, D. Martin

Targeting human central nervous system protein kinases: An isoform selective p38αMAPK inhibitor that attenuates disease progression in Alzheimer's disease mouse models.

DOI：
10.1021/acschemneuro.5b00002
发表时间：
2015-04-15
期刊：
ACS CHEMICAL NEUROSCIENCE
影响因子：
5
作者：
Roy, Saktimayee M.;Grum-Tokars, Valerie L.;Schavocky, James P.;Saeed, Faisal;Staniszewski, Agnieszka;Teich, Andrew F.;Arancio, Ottavio;Bachstetter, Adam D.;Webster, Scott J.;Van Eldik, Linda J.;Minasov, George;Anderson, Wayne F.;Pelletier, Jeffrey C.;Watterson, D. Martin
通讯作者：
Watterson, D. Martin

An isoform-selective p38α mitogen-activated protein kinase inhibitor rescues early entorhinal cortex dysfunctions in a mouse model of Alzheimer's disease.